The primary goal of this project is to contribute to a molecular level understanding of the biological and physiological events surrounding steroid synthesis, function and metabolism in natural and neoplastic processes. As a better understanding of these processes is achieved, rational drug design and endocrine therapy can contribute to the control of cancer and other diseases that are demonstrably endocrine related. The immediate aim of the project is to determine the exact molecular structures of a series of biologically important steroids and steroid complexes employing X-ray crystallographic techniques. Selection of candidates for analysis is based upon interdisciplinary collaboration with endocrinologists, pharmacologists, and biochemists. Emphasis will be placed on studies of sex hormones and antihormones implicated in breast cancer therapy, substrates for estrogen and androgen biosynthesis, competitive binders for adrenocorticoid and mineralocorticoid target proteins, and cardioactive steroids. Comparative analysis of the existing structural data is in progress in order to elucidate (a) the relationships between molecular conformations in solid and in solution, (b) relative potential energies of observed conformations, (c) interactions of steroids with their immediate environment, (d) mechanisms of estrogen and androgen biosynthesis, (e) relationships between steroid conformation and specificity of protein binding, and (f) correlations between conformational features and pharmacological activity. The long-term goal of this project is to establish structural reasons, such as ring distortions, stereospecific conformations, functional side chain orientations, or particular molecular stackings, for the biological specificity of steroids and for the explicit steroidal endocrine mechanisms which control neoplastic processes.